Institut de Recherche en Santé Digestive

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Levels of inflammatory mediators in circulation are known to increase with age, but the underlying cause of this age-associated inflammation is debated. We find that, when maintained under germ-free conditions, mice do not display an age-related increase in circulating pro-inflammatory cytokine levels. A higher proportion of germ-free mice live to 600 days than their conventional counterparts, and macrophages derived from aged germ-free mice maintain anti-microbial activity. Co-housing germ-free mice with old, but not young, conventionally raised mice increases pro-inflammatory cytokines in the blood. In tumor necrosis factor (TNF)-deficient mice, which are protected from age-associated inflammation, age-related microbiota changes are not observed. Furthermore, age-associated microbiota changes can be reversed by reducing TNF using anti-TNF therapy. These data suggest that aging-associated microbiota promote inflammation and that reversing these age-related microbiota changes represents a potential strategy for reducing age-associated inflammation and the accompanying morbidity.

It is increasingly perceived that gut host-microbial interactions are important elements in the pathogenesis of functional gastrointestinal disorders (FGID). The most convincing evidence to date is the finding that functional dyspepsia and irritable bowel syndrome (IBS) may develop in predisposed individuals following a bout of infectious gastroenteritis. There has been a great deal of interest in the potential clinical and therapeutic implications of small intestinal bacterial overgrowth in IBS. However, this theory has generated much debate because the evidence is largely based on breath tests which have not been validated. The introduction of culture-independent molecular techniques provides a major advancement in our understanding of the microbial community in FGID. Results from 16S rRNA-based microbiota profiling approaches demonstrate both quantitative and qualitative changes of mucosal and faecal gut microbiota, particularly in IBS. Investigators are also starting to measure host-microbial interactions in IBS. The current working hypothesis is that abnormal microbiota activate mucosal innate immune responses which increase epithelial permeability, activate nociceptive sensory pathways and dysregulate the enteric nervous system. While we await important insights in this field, the microbiota is already a therapeutic target. Existing controlled trials of dietary manipulation, prebiotics, probiotics, synbiotics and non-absorbable antibiotics are promising, although most are limited by suboptimal design and small sample size. In this article, the authors provide a critical review of current hypotheses regarding the pathogenetic involvement of microbiota in FGID and evaluate the results of microbiota-directed interventions. The authors also provide clinical guidance on modulation of gut microbiota in IBS.

Irritable bowel syndrome (IBS) and chronic idiopathic constipation ((CIC) also referred to as functional constipation) are two of the most common functional gastrointestinal disorders worldwide. IBS is a global problem, with anywhere from 5 to 15% of the general population experiencing symptoms that would satisfy a definition of IBS (1,2). In a systematic review on the global prevalence of IBS, Lovell and Ford (1) documented a pooled prevalence of 11% with all regions of the world suffering from this disorder at similar rates. Given its prevalence, the frequency of symptoms, and their associated debility for many patients and the fact that IBS typically occurs in younger adulthood, an important period for furthering education, embarking on careers, and/or raising families, the socioeconomic impact of IBS is considerable. These indirect medical costs are frequently compounded by the direct medical costs related to additional medical tests and the use of various medical and nonmedical remedies that may have limited impact. CIC is equally common; in another systematic review, Suares and Ford (3) reported a pooled prevalence of 14%, and also noted that constipation was more common in females, in older subjects, and those of lower socioeconomic status (3). Chronic constipation has also been linked to impaired quality of life (4), most notably among the elderly (5). Neither IBS nor CIC are associated with abnormal radiologic or endoscopic abnormalities, nor are they associated with a reliable biomarker; diagnosis currently rests entirely, therefore, on clinical grounds. Although a number of clinical definitions of both IBS and CIC have been proposed, the criteria developed through the Rome process, currently in its third iteration, have been those most widely employed in clinical trials and, therefore, most relevant to any review of the literature on the management of these disorders. According to Rome III, IBS is defined on the basis of the presence of: Recurrent abdominal pain or discomfort at least 3 days/month in the past 3 months associated with two or more of the following: Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form (appearance) of stool These criteria should be fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis (6). Rome III defines functional constipation as: the presence of two or more of the following: Straining during at least 25% of defecations Lumpy or hard stools in at least 25% of defecations Sensation of incomplete evacuation for at least 25% of defecations Sensation of anorectal obstruction/blockage for at least 25% of defecations Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor) Fewer than three defecations per week Furthermore, loose stools are rarely present without the use of laxatives and there are insufficient criteria for IBS. Again, these criteria should be fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis (6). In Rome III, IBS is subtyped according to predominant bowel habit as IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed and definition of bowel habit in on the of stool form by to the that IBS according to predominant bowel with that and may be to the of at of these is that symptoms may be a and may IBS during a and a IBS during another period in their there is general of the Rome they are employed in the of IBS and CIC in clinical more as as to of that the Rome process, of the definitions in systematic IBS is defined abdominal discomfort associated with bowel is defined as: a disorder defined as defecation and is by stool or stool a of incomplete evacuation, to or for maneuvers to CIC is defined as the presence of these symptoms for at least 3 months is important to that the Rome III criteria that with chronic constipation criteria for IBS, with pain or discomfort a in the In a CIC and IBS with constipation may be and have these also a for patients to these is that in this of of on IBS and these be in the of this therefore, was to the most systematic by the of on IBS from and CIC from have a of systematic on the of in IBS and have been systematic of for IBS and CIC in the past 5 have been in the and therefore, all these systematic of IBS and CIC and the the from of this was to the of in IBS and CIC with or the of in IBS according to predominant stool reported with IBS with and mixed as as with for both IBS and review that any definition of IBS or IBS, this a the criteria the or Rome or III this symptoms by any of the Rome criteria as as a trials with or trials for at the of the before IBS, the and that the the and laxatives to be for at least be trials to or more of the of in IBS or CIC symptoms Improvement in abdominal pain for IBS IBS symptom or abdominal pain for IBS number of stools per week during for CIC for of to and to and the of trials on IBS with the bowel syndrome and functional as medical and and IBS, and functional bowel of these the with with the or as and or the or of and these the with with the or as and or the or of these the with with the or as and of and these the with with the and or and of these the with with the or as and or the or of these the with with the or as and or the or of and these the with with the or as and or the or of these the with with the or as and or the or of these the with with the or of these the with with the as a and on CIC with the constipation or gastrointestinal as and or functional idiopathic chronic or the the pelvic and also of these the with with the or as and or the or of and these the with with the as and or the of and of these the with with the or as and or the or of these the with with the or of these the with with the and and the or of these the with with the or of these the with with the or as and of and these the with with the and or and was limited to with to of of the of relevant was also and and of that for and to in the for on for of according to the in the the to the to of of and of an and by the and by a on to developed was by the two in to a as all to be IBS, any of global IBS symptoms as a was as the this was in abdominal pain was any of global CIC symptoms as a was as the impact of was as a of IBS or CIC symptoms with there the and to a more of the of IBS as global IBS symptom or IBS symptom a with was should be noted that may be in IBS or CIC of the on than global symptoms or abdominal this was and was of the of this of reported the of was and/or the for this by in or in or of tests for number to is the number of patients would to and the for to an in symptoms, and the number to is the number of patients would to and the for to an as the of the from the and the is and is for of and the of and for the quality of and of for medical has been widely in and is by all gastrointestinal quality of the is on the as as the of of and that for the the of is as to on the to would change the of also as or according to the quality of the to all of and and this the or should be to most and or are to change in the of a that to most patients in most and is to change in the of of the for IBS is in the for the on the quality of that in and the for the of in the of the for CIC is in the for the on quality of the in and the for the of in of the of the quality of of of on for for quality of of for IBS according to for of for IBS according to of of on for for quality of of of on CIC according to for of for of CIC according to Irritable bowel syndrome and in IBS of in Although is of the most common of symptoms in IBS to and with of the have typically in the of a on their IBS have their to this or from IBS patients that they have an to are in IBS the prevalence of in is and in of gastrointestinal patients that that their symptoms or IBS symptoms to of patients the in a on their with and a of to a have that a of IBS patients to an that may their of in may symptoms in IBS of that in IBS to of relevant symptom and an week three patients of these 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insufficient to a on the use of or in IBS, a for with and to be the that and the to on to as as a of to a or at this for this by the and has in IBS and to be and, the or use of an has at least the in has been in IBS have been for on an basis in the of IBS on the that and to IBS symptoms and pain in the and in IBS. are more common with than of patients with IBS. was the and and 3 criteria or all IBS, the fact that most trials before Rome definitions of trials the of IBS patients the quality of trials was with more than trials reported an of and reported on of all of was in all of the the in the various and are in the review that as a has a in IBS symptoms with the of 5 the of is and to as there are a number of of the for to and with of and of these in as as and for those that in was a in and have a on IBS symptoms, the of patients trials in this review reported with or In of patients to with of to the of was among those as with of experiencing any with the of most common and there reported in in any of the Although many of the relevant clinical trials are and from in of as a are in IBS, their use may be limited by all have been to be and on in quality and Furthermore, the of of the more may be limited to in IBS be in various through or that may also have of and of pain and its use for the of IBS. is to in IBS of is with than with of trials the of IBS patients with on this was at of with the reported a of on IBS symptoms with this was there was a in of with with the of 3 there was In these an of was employed in from to the of was among those as with of experiencing any In may be is in IBS. in IBS is insufficient to for use in IBS. of two was in of with trials the of IBS patients with patients and the on in both in in and in of the Although is an there is to support the use of for of global symptoms in IBS. in IBS the management of IBS on the that and among IBS in and that in these in pain of and are in symptom in IBS. are common and may of systematic review and 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These are and should be noted that has been widely from the in and that this was to be more than in a of trials patients for or trials patients with IBS and mixed IBS quality of trials was of all and mixed for the of IBS and was In of in or mixed IBS nor was in with mixed as with the various and to that have been developed and in IBS, and both are in regions and by of of the use of in the is limited to with IBS and be in the of a is for the management of IBS in and is to for the of IBS. of is a similar to in the are that in the of and by and on the of of in an of that a of to the of the that in of and the by and the as as of pain clinical trials in IBS patients patients trials at of and there was was a in of with with the of 6 with was a in of with on abdominal pain of with on by two of the three trials among those with reported in all three was more with as with with the of 6 reported in two trials was also more common with with the of is to for the of IBS. of the on the of the in and the in through the and clinical trials of in IBS patients have been reported in three of these was a mixed population of IBS and CIC patients reported in IBS patients trials at of was a in of as with with the of and the three quality of was as according to as the on IBS symptoms was and the for the was to a Furthermore, for IBS patients from on reported in all three pooled for the two trials reported in a In the by reported by of patients as with of this was was also with with with this was more frequently among those was diarrhea In the two that pooled and of IBS patients and reported at least in of patients with of those was reported by of those to with of those to and are in IBS. both of these in with than their in an IBS for those have or as is to and by of on should be in IBS, the of on in IBS is that symptoms and pain in patients with IBS. of is a that as an and is by the for the of has been in patients with in with that stool frequency pain two of in IBS. In there was on bowel or discomfort and pain In the patients with IBS with the in bowel was with with at there was in on abdominal pain or defined as more than bowel per week with an of two or more from and of abdominal pain or with with there was in the of patients with a pain defined as a by or more from with most of these or is that pain or symptom in IBS. Chronic idiopathic constipation in CIC and stool frequency in patients with chronic idiopathic of is defined as that are of in the and are to the be of or and as a is as or on its with is the is is the of the in as from the in the and to and have been with in CIC and the quality of the use of these is trials the criteria for in this review a was with three trials and the be of or a to for with the was of the trials three and the a of and in and in the from the three trials that was with with the of and Although these trials be for the definitions of all and in all patients in the the that was to present at in this to be with In of among the three trials that the by these all reported with of a of and as a and reported in the of patients with during of incomplete evacuation, or of with In the number of bowel was also trials reported on the of in CIC patients to of per or noted with was reported reported the number of patients in of with and two with with of patients experiencing abdominal pain with of in or there symptom for gastrointestinal as abdominal and with with and in are in the management of chronic and and may the use of in are and laxatives in CIC laxatives or that in the with frequency and laxatives in is in symptoms of of is in symptoms of of with reported in patients with the of 3 trials at of and there was with in with the of trials at of and there was with laxatives on the number of reported the of abdominal or and laxatives in and are in of laxatives to and by the or in the a bowel laxatives and trials of reported and a of In of all patients to laxatives to to as with of those with the of 3 and with reported of the of experiencing any with laxatives was more frequently in the two trials Although by of the laxatives and and the laxatives and have been to be in chronic by have been and be at this laxatives have been in CIC is more than in symptoms of of a in the gastrointestinal and and are of of the the and gastrointestinal has the to symptoms 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pelvic they a relevant or or they with or of three clinical trials that patients that to a or trials or at of of to to the of the or a of of to the or was a of constipation with the of and of the trials reported on Although may in by a and in in the management of patients with CIC have of pelvic to the of this for many patients and their in CIC is a for as for CIC is the most important of the the of in the in and in the the has been as a for 3 of the in CIC patients three trials at of of employed from as as to as as In the to an of bowel per week for of the of the was reported for and of those to and of with for was more common in the patients with in CIC is insufficient to in of three trials in CIC patients of the trials the of or and was an In two trials the of was to be and a of two trials that reported on in constipation in CIC Although both trials in of the pooled in a as there was the two two trials that reported on number of bowel per week in was a in the number of bowel per week in bowel per week in the

Inflammatory bowel disease (IBD) encompasses a range of intestinal pathologies, the most common of which are ulcerative colitis (UC) and Crohn's Disease (CD). Both UC and CD, when present in the colon, generate a similar symptom profile which can include diarrhea, rectal bleeding, abdominal pain, and weight loss.(1) Although the pathogenesis of IBD remains unknown, it is described as a multifactorial disease that involves both genetic and environmental components.(2) There are numerous and variable animal models of colonic inflammation that resemble several features of IBD. Animal models of colitis range from those arising spontaneously in susceptible strains of certain species to those requiring administration of specific concentrations of colitis-inducing chemicals, such as dextran sulphate sodium (DSS). Chemical-induced models of gut inflammation are the most commonly used and best described models of IBD. Administration of DSS in drinking water produces acute or chronic colitis depending on the administration protocol.(3) Animals given DSS exhibit weight loss and signs of loose stool or diarrhea, sometimes with evidence of rectal bleeding.(4,5) Here, we describe the methods by which colitis development and the resulting inflammatory response can be characterized following administration of DSS. These methods include histological analysis of hematoxylin/eosin stained colon sections, measurement of pro-inflammatory cytokines, and determination of myeloperoxidase (MPO) activity, which can be used as a surrogate marker of inflammation.(6) The extent of the inflammatory response in disease state can be assessed by the presence of clinical symptoms or by alteration in histology in mucosal tissue. Colonic histological damage is assessed by using a scoring system that considers loss of crypt architecture, inflammatory cell infiltration, muscle thickening, goblet cell depletion, and crypt abscess.(7) Quantitatively, levels of pro-inflammatory cytokines with acute inflammatory properties, such as interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α,can be determined using conventional ELISA methods. In addition, MPO activity can be measured using a colorimetric assay and used as an index of inflammation.(8) In experimental colitis, disease severity is often correlated with an increase in MPO activity and higher levels of pro-inflammatory cytokines. Colitis severity and inflammation-associated damage can be assessed by examining stool consistency and bleeding, in addition to assessing the histopathological state of the intestine using hematoxylin/eosin stained colonic tissue sections. Colonic tissue fragments can be used to determine MPO activity and cytokine production. Taken together, these measures can be used to evaluate the intestinal inflammatory response in animal models of experimental colitis.

The Lyon Consensus provides conclusive criteria for and against the diagnosis of gastro-oesophageal reflux disease (GERD), and adjunctive metrics that consolidate or refute GERD diagnosis when primary criteria are borderline or inconclusive. An international core and working group was assembled to evaluate research since publication of the original Lyon Consensus, and to vote on statements collaboratively developed to update criteria. The Lyon Consensus 2.0 provides a modern definition of actionable GERD, where evidence from oesophageal testing supports revising, escalating or personalising GERD management for the symptomatic patient. Symptoms that have a high versus low likelihood of relationship to reflux episodes are described. Unproven versus proven GERD define diagnostic strategies and testing options. Patients with no prior GERD evidence (unproven GERD) are studied using prolonged wireless pH monitoring or catheter-based pH or pH-monitoring off antisecretory medication, while patients with conclusive GERD evidence (proven GERD) and persisting symptoms are evaluated using pH-impedance monitoring while on optimised antisecretory therapy. The major changes from the original Lyon Consensus criteria include establishment of Los Angeles grade B oesophagitis as conclusive GERD evidence, description of metrics and thresholds to be used with prolonged wireless pH monitoring, and inclusion of parameters useful in diagnosis of refractory GERD when testing is performed on antisecretory therapy in proven GERD. Criteria that have not performed well in the diagnosis of actionable GERD have been retired. Personalisation of investigation and management to each patient's unique presentation will optimise GERD diagnosis and management.

Laparoscopic cholecystectomy quickly emerged as an alternative to open cholecystectomy. However its safety, efficacy, and morbidity have yet to be fully evaluated. During the first 6 months of 1990, we performed 100 consecutive laparoscopic cholecystectomies with no deaths and a morbidity rate of 8% (8 of 100 patients; 4 major, 4 minor). There were 81 women and 19 men, with a mean age of 46.1 years (range, 17 to 84 years). All patients had a preoperative history consistent with symptomatic biliary tract disease, and most had proved gallstones by sonography. This included four patients with acute cholecystitis. Mean operating time improved significantly from month 1 to month 6 (122 +/- 45.4 minutes versus 78.5 +/- 30 minutes, respectively), indicating a rapid learning curve. Mean hospital stay was 27.6 hours, reflecting a policy of overnight stay. Postoperative narcotic requirements were limited to oral or no medications in more than 70% of patients. A regular diet was tolerated by 83% of the patients by the morning following the procedure. Median time of return to full activity was 12.8 +/- 6.8 days after operation. In addition analysis of the hospital costs of these 100 cases demonstrates a modest cost advantage over standard open cholecystectomy (n = 58) (mean, $3620.25 +/- $1005.00 versus $4251.76 +/- $988.00). There was one minor bile duct injury requiring laparotomy and t-tube insertion, two postoperative bile collections, and one clinical diagnosis of a retained stone that passed spontaneously. Four patients required conversion to open cholecystectomy because of technical difficulties with the dissection. Although there is a significant learning curve, laparoscopic cholecystectomy is a safe and effective procedure that can be performed with minimal risk. Laparoscopic cholecystectomy should be performed by surgeons who are trained in biliary surgery and knowledgeable in biliary anatomy, and, as with all operations, it should be performed with meticulous attention to technique.

The stomach is traditionally regarded as a hollow muscular sac that initiates the second phase of digestion. Yet this simple view ignores the fact that it is the most sophisticated endocrine organ with unique physiology, biochemistry, immunology and microbiology. All ingested materials, including our nutrition, have to negotiate this organ first, and as such, the stomach is arguably the most important segment within the GI tract. The unique biological function of gastric acid secretion not only initiates the digestive process but also acts as a first line of defence against food-borne microbes. Normal gastric physiology and morphology may be disrupted by Helicobacter pylori infection, the most common chronic bacterial infection in the world and the aetiological agent for most peptic ulcers and gastric cancer. In this state-of-the-art review, the most relevant new aspects of the stomach in health and disease are addressed. Topics include gastric physiology and the role of gastric dysmotility in dyspepsia and gastroparesis; the stomach in appetite control and obesity; there is an update on the immunology of the stomach and the emerging field of the gastric microbiome. H. pylori-induced gastritis and its associated diseases including peptic ulcers and gastric cancer are addressed together with advances in diagnosis. The conclusions provide a future approach to gastric diseases underpinned by the concept that a healthy stomach is the gateway to a healthy and balanced host. This philosophy should reinforce any public health efforts designed to eradicate major gastric diseases, including stomach cancer.

OBJECTIVES: The objective of this study was to evaluate prospectively the efficacy of different strategies based on endoscopic ultrasonography (EUS), helical computed tomography (CT), magnetic resonance imaging (MRI), and angiography (A) in the staging and tumor resectability assessment of pancreatic cancer. METHODS: All consecutive patients with pancreatic carcinoma judged fit for laparotomy were studied by EUS, CT, MRI, and A. Results of each of the imaging techniques regarding primary tumor, locoregional extension, lymph-node involvement, vascular invasion, distant metastases, tumor TNM stage, and tumor resectability were compared with the surgical findings. Univariate, logistic regression, decision, and cost minimization analyses were performed. RESULTS: Sixty-two patients with pancreatic cancer were included. Helical CT had the highest accuracy in assessing extent of primary tumor (73%), locoregional extension (74%), vascular invasion (83%), distant metastases (88%), tumor TNM stage (46%), and tumor resectability (83%), whereas EUS had the highest accuracy in assessing tumor size (r = 0.85) and lymph node involvement (65%). The decision analysis demonstrated that the best strategy to assess tumor resectability was based on CT or EUS as initial test, followed by the alternative technique in those potentially resectable cases. Cost minimization analysis favored the sequential strategy in which EUS was used as a confirmatory technique in those patients in whom helical CT suggested resectability of the tumor. CONCLUSIONS: Helical CT and EUS are the most useful individual imaging techniques in the staging of pancreatic cancer. In those cases with potentially resectable tumors a sequential approach consisting of helical CT as an initial test and EUS as a confirmatory technique seems to be the most reliable and cost minimization strategy.

Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to the expectation of effective antifibrotic drugs, yet none has been approved. Thus, an assessment of the field is timely, to clarify priorities and accelerate progress. Here, we highlight the successes to date but, more importantly, identify gaps and unmet needs, both experimentally and clinically. These include the need to better define cell-cell interactions and etiology-specific elements of fibrogenesis and their link to disease-specific drivers of portal hypertension. Success in treating viral hepatitis has revealed the remarkable capacity of the liver to degrade scar in reversing fibrosis, yet we know little of the mechanisms underlying this response. Thus, there is an exigent need to clarify the cellular and molecular mechanisms of fibrosis regression in order for therapeutics to mimic the liver's endogenous capacity. Better refined and more predictive in vitro and animal models will hasten drug development. From a clinical perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate to supplant biopsy. More urgently, digital pathology methods that leverage machine learning and artificial intelligence must be validated in order to capture more prognostic information from liver biopsies and better quantify the response to therapies. For more refined treatment of NASH, orthogonal approaches that integrate genetic, clinical, and pathological data sets may yield treatments for specific subphenotypes of the disease. Collectively, these and other advances will strengthen and streamline clinical trials and better link histologic responses to clinical outcomes.

OBJECTIVE: Dietary triggers such as gluten and highly fermentable oligo-, di- and monosaccharides and polyols (FODMAP)-containing foods have been associated with worsening irritable bowel syndrome (IBS) symptoms. However, the true impact of dietary restriction on IBS symptoms has remained unclear. The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) examining the efficacy of exclusion diets (we focused on low FODMAP and gluten-free diets (GFD)) in IBS. METHODS: We conducted a search of the literature using the electronic databases MEDLINE (1946 to November 2017), EMBASE (1974 to November 2017), Cochrane Central Register of Controlled Trials (November 2017), and Cochrane Database of Systematic Reviews (2005 to November, 2017) for RCTs of exclusion diets in IBS. Two independent reviewers screened citations and a third reviewer resolved disagreement. Two independent reviewers performed eligibility assessment and data abstraction. For inclusion, RCTs that evaluated an exclusion diet versus an alternative or usual diet and assessed improvement in either global IBS symptoms or abdominal pain were required. Data were synthesized as relative risk of symptoms remaining using a random effects model. Quality of evidence was assessed using GRADE methodology. RESULTS: A total of 1726 citations were identified. After full-text screening a total of nine studies were eligible for the systematic review. There were two RCTs of a GFD, involving 111 participants. Both selected patients who responded to a GFD and then randomized them to continue the diet or have the diet “spiked” with gluten. A GFD was associated with reduced global symptoms compared with a control diet (RR = 0.42; 95% CI 0.11 to 1.55;I2 = 88%), although this was not statistically significant. There were seven RCTs comparing a low FODMAP diet with various control interventions in 397 participants. A low FODMAP diet was associated with reduced global symptoms compared with control interventions (RR = 0.69; 95% CI 0.54 to 0.88;I2 = 25%). The three RCTS that compared low FODMAP diet with rigorous control diets had the least heterogeneity between studies, but also the least magnitude of effect. The overall quality of the data was “very low” according to GRADE criteria. CONCLUSIONS: There is insufficient evidence to recommend a GFD to reduce IBS symptoms. There is very low quality evidence that a low FODMAP diet is effective in reducing symptoms in IBS patients.

OBJECTIVE: To evaluate the relation between intake of ultra-processed food and risk of inflammatory bowel disease (IBD). DESIGN: Prospective cohort study. SETTING: 21 low, middle, and high income countries across seven geographical regions (Europe and North America, South America, Africa, Middle East, south Asia, South East Asia, and China). PARTICIPANTS: 116 087 adults aged 35-70 years with at least one cycle of follow-up and complete baseline food frequency questionnaire (FFQ) data (country specific validated FFQs were used to document baseline dietary intake). Participants were followed prospectively at least every three years. MAIN OUTCOME MEASURES: The main outcome was development of IBD, including Crohn's disease or ulcerative colitis. Associations between ultra-processed food intake and risk of IBD were assessed using Cox proportional hazard multivariable models. Results are presented as hazard ratios with 95% confidence intervals. RESULTS: Participants were enrolled in the study between 2003 and 2016. During the median follow-up of 9.7 years (interquartile range 8.9-11.2 years), 467 participants developed incident IBD (90 with Crohn's disease and 377 with ulcerative colitis). After adjustment for potential confounding factors, higher intake of ultra-processed food was associated with a higher risk of incident IBD (hazard ratio 1.82, 95% confidence interval 1.22 to 2.72 for ≥5 servings/day and 1.67, 1.18 to 2.37 for 1-4 servings/day compared with <1 serving/day, P=0.006 for trend). Different subgroups of ultra-processed food, including soft drinks, refined sweetened foods, salty snacks, and processed meat, each were associated with higher hazard ratios for IBD. Results were consistent for Crohn's disease and ulcerative colitis with low heterogeneity. Intakes of white meat, red meat, dairy, starch, and fruit, vegetables, and legumes were not associated with incident IBD. CONCLUSIONS: Higher intake of ultra-processed food was positively associated with risk of IBD. Further studies are needed to identify the contributory factors within ultra-processed foods. STUDY REGISTRATION: ClinicalTrials.gov NCT03225586.

The mechanisms by which enteropathogenic Escherichia coli (EPEC), an important cause of diarrhea among infants in developing countries, induce symptoms are not defined. EPEC have a type III secretion system required for characteristic attaching and effacing changes that modify the cytoskeleton and apical surface of host cells. Infection of polarized intestinal epithelial cell monolayers by EPEC leads to a loss of transepithelial electrical resistance, which also requires the type III secretion system. We demonstrate here that EspF, a protein that is secreted by EPEC via the type III secretion system, is not required for quantitatively and qualitatively typical attaching and effacing lesion formation in intestinal epithelial cells. However, EspF is required in a dose-dependent fashion for the loss of transepithelial electrical resistance, for increased monolayer permeability, and for redistribution of the tight junction-associated protein occludin. Furthermore, the analysis of EPEC strains expressing EspF-adenylate cyclase fusion proteins indicates that EspF is translocated via the type III secretion system to the cytoplasm of host cells, a result confirmed by immunofluorescence microscopy. These studies suggest a novel role for EspF as an effector protein that disrupts intestinal barrier function without involvement in attaching and effacing lesion formation.

BACKGROUND: Changes in gut microbiota composition and activity have been associated with different metabolic disorders, including obesity, diabetes, and cardiometabolic disorders. Recent evidence suggests that different organs are directly under the influence of bacterial metabolites that may directly or indirectly regulate physiological and pathological processes. SCOPE OF REVIEW: We reviewed seminal as well as recent papers showing that gut microbes influence energy, glucose and lipid homeostasis by controlling different metabolic routes such as endocrine, enteric and central nervous system. These dialogues are discussed in the context of obesity and diabetes but also for brain pathologies and neurodegenerative disorders. MAJOR CONCLUSIONS: The recent advances in gut microbiota investigation as well as the discovery of specific metabolites interacting with host cells has led to the identification of novel inter-organ communication during metabolic disturbances. This suggests that gut microbes may be viewed as "novel" future therapeutic partners. This article is part of a special issue on microbiota.

The growing demand for liver transplantation and the concomitant scarcity of cadaveric livers have increased the need for living donor liver transplantation (LDLT). Ensuring the safety of donors and recipients is critical. The preoperative identification of the vascular and biliary tract anatomy with 3-dimensional (3D) printing may allow better preoperative surgical planning, avert unnecessary surgery in patients with potentially unsuitable anatomy, and thereby decrease the complications of liver transplant surgery. We developed a protocol and successfully 3D-printed synthetic livers (along with their complex networks of vascular and biliary structures) replicating the native livers of 6 patients: 3 living donors and 3 respective recipients who underwent LDLT. To our knowledge, these are the first complete 3D-printed livers. Using standardized preoperative, intraoperative, and postoperative assessments, we demonstrated identical anatomical and geometrical landmarks in the 3D-printed models and native livers.

Objective Roseburia intestinalis is a probiotic species that can suppress intestinal inflammation by producing metabolites. We aimed to study the role of R. intestinalis in colorectal tumourigenesis and immunotherapy. Design R. intestinalis abundance was evaluated in stools of patients with colorectal cancer (CRC) (n=444) and healthy controls (n=575). The effects of R. intestinalis were studied in Apc Min/+ or azoxymethane (AOM)-induced CRC mouse models, and in syngeneic mouse xenograft models of CT26 (microsatellite instability (MSI)-low) or MC38 (MSI-high). The change of immune landscape was evaluated by multicolour flow cytometry and immunohistochemistry staining. Metabolites were profiled by metabolomic profiling. Results R. intestinalis was significantly depleted in stools of patients with CRC compared with healthy controls. R. intestinalis administration significantly inhibited tumour formation in Apc Min/+ mice, which was confirmed in mice with AOM-induced CRC. R. intestinalis restored gut barrier function as indicated by improved intestinal permeability and enhanced expression of tight junction proteins. Butyrate was identified as the functional metabolite generated by R. intestinalis. R. intestinalis or butyrate suppressed tumour growth by inducing cytotoxic granzyme B + , interferon (IFN)-γ + and tumour necrosis factor (TNF)-α + CD8 + T cells in orthotopic mouse models of MC38 or CT26. R. intestinalis or butyrate also significantly improved antiprogrammed cell death protein 1 (anti-PD-1) efficacy in mice bearing MSI-low CT26 tumours. Mechanistically, butyrate directly bound to toll-like receptor 5 (TLR5) receptor on CD8 + T cells to induce its activity through activating nuclear factor kappa B (NF-κB) signalling. Conclusion R. intestinalis protects against colorectal tumourigenesis by producing butyrate, which could also improve anti-PD-1 efficacy by inducing functional CD8 + T cells. R. intestinalis is a potential adjuvant to augment anti-PD-1 efficacy against CRC.

BACKGROUND: The human gut houses one of the most complex and abundant ecosystems composed of up to 10(13)-10(14) microorganisms. The importance of this intestinal microbiota is highlighted when a disruption of the intestinal ecosystem equilibrium appears (a phenomenon called dysbiosis) leading to an illness status, such as inflammatory bowel diseases (IBD). Indeed, the reduction of the commensal bacterium Faecalibacterium prausnitzii (one of the most prevalent intestinal bacterial species in healthy adults) has been correlated with several diseases, including IBD, and most importantly, it has been shown that this bacterium has anti-inflammatory and protective effects in pre-clinical models of colitis. Some dysbiosis disorders are characterized by functional and physiological alterations. Here, we report the beneficial effects of F. prausnitzii in the physiological changes induced by a chronic low-grade inflammation in a murine model. Chronic low-grade inflammation and gut dysfunction were induced in mice by two episodes of dinitro-benzene sulfonic acid (DNBS) instillations. Markers of inflammation, gut permeability, colonic serotonin and cytokine levels were studied. The effects of F. prausnitzii strain A2-165 and its culture supernatant (SN) were then investigated. RESULTS: No significant differences were observed in classical inflammation markers confirming that inflammation was subclinical. However, gut permeability, colonic serotonin levels and the colonic levels of the cytokines IL-6, INF-γ, IL-4 and IL-22 were higher in DNBS-treated than in untreated mice. Importantly, mice treated with either F. prausnitzii or its SN exhibited significant decreases in intestinal permeability, tissue cytokines and serotonin levels. CONCLUSIONS: Our results show that F. prausnitzii and its SN had beneficial effects on intestinal epithelial barrier impairment in a chronic low-grade inflammation model. These observations confirm the potential of this bacterium as a novel probiotic treatment in the management of gut dysfunction and low-grade inflammation.

The gut microbiome is considered an organ contributing to the regulation of host metabolism. Since the relationship between the gut microbiome and specific diseases was elucidated, numerous studies have deciphered molecular mechanisms explaining how gut bacteria interact with host cells and eventually shape metabolism. Both metagenomic and metabolomic analyses have contributed to the discovery of bacterial-derived metabolites acting on host cells. In this review, we examine the molecular mechanisms by which bacterial metabolites act as paracrine or endocrine factors, thereby regulating host metabolism. We highlight the impact of specific short-chain fatty acids on the secretion of gut peptides (i.e., glucagon-like peptide-1, peptide YY) and other metabolites produced from different amino acids and regulating inflammation, glucose metabolism, or energy homeostasis. We also discuss the role of gut microbes on the regulation of bioactive lipids that belong to the endocannabinoid system and specific neurotransmitters (e.g., γ-aminobutyric acid, serotonin, nitric oxide). Finally, we review the role of specific bacterial components (i.e., ClpB, Amuc_1100) also acting as endocrine factors and eventually controlling host metabolism. In conclusion, this review summarizes the recent state of the art, aiming at providing evidence that the gut microbiome influences host endocrine functions via several bacteria-derived metabolites.

BACKGROUND: Changes in hygiene and dietary habits, including increased consumption of foods high in fat, simple sugars, and salt that are known to impact the composition and function of the intestinal microbiota, may explain the increase in prevalence of chronic inflammatory diseases. High salt consumption has been shown to worsen autoimmune encephalomyelitis and colitis in mouse models through p38/MAPK signaling pathway. However, the effect of high salt diet (HSD) on gut microbiota and on intestinal immune homeostasis, and their roles in determining vulnerability to intestinal inflammatory stimuli are unknown. Here, we investigate the role of gut microbiota alterations induced by HSD on the severity of murine experimental colitis. RESULTS: Compared to control diet, HSD altered fecal microbiota composition and function, reducing Lactobacillus sp. relative abundance and butyrate production. Moreover, HSD affected the colonic, and to a lesser extent small intestine mucosal immunity by enhancing the expression of pro-inflammatory genes such as Rac1, Map2k1, Map2k6, Atf2, while suppressing many cytokine and chemokine genes, such as Ccl3, Ccl4, Cxcl2, Cxcr4, Ccr7. Conventionally raised mice fed with HSD developed more severe DSS- (dextran sodium sulfate) and DNBS- (dinitrobenzene sulfonic acid) induced colitis compared to mice on control diet, and this effect was absent in germ-free mice. Transfer experiments into germ-free mice indicated that the HSD-associated microbiota profile is critically dependent on continued exposure to dietary salt. CONCLUSIONS: Our results indicate that the exacerbation of colitis induced by HSD is associated with reduction in Lactobacillus sp. and protective short-chain fatty acid production, as well as changes in host immune status. We hypothesize that these changes alter gut immune homeostasis and lead to increased vulnerability to inflammatory insults.

BACKGROUND: Short chain fatty acid (SCFA) deficiency is associated with colitis in animals and humans, and the mucosal metabolism of these compounds is decreased in ulcerative colitis. AIMS: To assess the efficacy of topical SCFA treatment in ulcerative colitis. PATIENTS AND METHODS: 103 patients with distal ulcerative colitis were entered into a six week, double-blind, placebo controlled trial of rectal SCFA twice daily; patients who were unchanged on placebo were offered SCFA in an open-label extension trial. RESULTS: Of the 91 patients completing the trial, more patients in the SCFA treated than in the placebo treated group improved (33% v 20%, p = 0.14, NS). Those on SCFA also had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores. In patients with a relatively short current episode of colitis (< 6 months, n = 42), more responded to SCFA than to placebo (48% v 18%, p = 0.03). These patients also had larger, but statistically non-significant, decreases in their clinical activity index (p = 0.08 v placebo). Every patient who improved used at least five of six of the prescribed rectal SCFA irrigations, whereas only 37% who did not improve were as compliant. In the open-label extension trial, 65% improved on SCFA; these patients also had significant reductions (p < 0.02) in their clinical and histological activity scores. CONCLUSIONS: Although SCFA enemas were not of therapeutic value in this controlled trial, the results suggest efficacy in subsets of patients with distal ulcerative colitis including those with short active episodes. Prolonged contact with rectal mucosa seems to be necessary for therapeutic benefit.